title: The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells.
abstract: Mouse haematopoietic stem cells (HSCs) undergo a postnatal transition in several properties, including a marked reduction in their self-renewal activity. We now show that the developmentally timed change in this key function of HSCs is associated with their decreased expression of Lin28b and an accompanying increase in their let-7 microRNA levels. Lentivirus-mediated overexpression of Lin28 in adult HSCs elevates their self-renewal activity in transplanted irradiated hosts, as does overexpression of Hmga2, a well-established let-7 target that is upregulated in fetal HSCs. Conversely, HSCs from fetal Hmga2(-/-) mice do not exhibit the heightened self-renewal activity that is characteristic of wild-type fetal HSCs. Interestingly, overexpression of Hmga2 in adult HSCs does not mimic the ability of elevated Lin28 to activate a fetal lymphoid differentiation program. Thus, Lin28b may act as a master regulator of developmentally timed changes in HSC programs with Hmga2 serving as its specific downstream modulator of HSC self-renewal potential.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Copley
authors.forename: Sonja
authors.initials: S
authors.lastname: Babovic
authors.forename: Claudia
authors.initials: C
authors.lastname: Benz
authors.forename: David J H F
authors.initials: DJ
authors.lastname: Knapp
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.forename: David G
authors.initials: DG
authors.lastname: Kent
authors.forename: Stefan
authors.initials: S
authors.lastname: Wohrer
authors.forename: David Q
authors.initials: DQ
authors.lastname: Treloar
authors.forename: Christopher
authors.initials: C
authors.lastname: Day
authors.forename: Keegan
authors.initials: K
authors.lastname: Rowe
authors.forename: Heidi
authors.initials: H
authors.lastname: Mader
authors.forename: Florian
authors.initials: F
authors.lastname: Kuchenbauer
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005333:Fetus; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D025743:HMGA2 Protein; C516326:LIN28B protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse